Submissions for variant NM_000443.4(ABCB4):c.140G>A (p.Arg47Gln)

gnomAD frequency: 0.00006  dbSNP: rs372685632

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724891	SCV000230097	uncertain significance	not provided	2018-03-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000391687	SCV000470170	uncertain significance	Low phospholipid associated cholelithiasis	2017-04-27	criteria provided, single submitter	clinical testing	The ABCB4 c.140G>A (p.Arg47Gln) variant is a missense variant that has been reported in at least two studies, where it was found in a compound heterozygous state in two individuals with low-phospholipid associated cholestasis syndrome (Wendum et al. 2012; Poupon et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg47Gln variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for ABCB4-related intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000724891	SCV000617822	uncertain significance	not provided	2017-06-28	criteria provided, single submitter	clinical testing	The R47Q variant has been reported previously in patients with PFIC3, LPAC, and IPC who also harbored another ABCB4 gene variant (Davit-Spraul et al., 2010; Poupon et al., 2013; Frider et al., 2015). Expression studies revealed that R47Q is associated with reduced protein levels compared to wild-type, however R47Q was not associated with altered protein localization (Frider et al., 2015). The R47Q variant is observed in 2/11396 (0.02%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R47Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Center for Human Genetics Tuebingen	RCV000724891	SCV002062759	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282001	SCV002572191	likely pathogenic	Progressive familial intrahepatic cholestasis	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: ABCB4 c.140G>A (p.Arg47Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250894 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (8.8e-05 vs 0.0022), allowing no conclusion about variant significance. c.140G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with features of Familial Intrahepatic Cholestasis, namely Low phospholipid-associated cholelithiasis (LPAC)/cholestatic liver disease/Intrahepatic cholestasis of pregnancy (ICP) (example, Poupon_2010, Wendum_2012, Frider_2015, Dixon_2017, Schatz_2018, Huynh_2019, Khabou_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting that the variant does not alter localization but leads to reduced protein levels (Frider_2015). The following publications have been ascertained in the context of this evaluation (PMID: 28924228, 26256905, 31538484, 31181191, 20537830, 29761167, 22331132). ClinVar contains an entry for this variant (Variation ID: 197144). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000724891	SCV003440063	likely pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 47 of the ABCB4 protein (p.Arg47Gln). This variant is present in population databases (rs372685632, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of autosomal recessive ABCB4-related conditions (PMID: 20537830, 23533021, 26256905, 28924228, 29761167, 30449124, 31181191, 31538484). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197144). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB4 protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26256905, 31181191). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV003343674	SCV004061512	uncertain significance	Inborn genetic diseases	2023-06-26	criteria provided, single submitter	clinical testing	The c.140G>A (p.R47Q) alteration is located in exon 4 (coding exon 3) of the ABCB4 gene. This alteration results from a G to A substitution at nucleotide position 140, causing the arginine (R) at amino acid position 47 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.009% (22/250894) total alleles studied. The highest observed frequency was 0.049% (3/6110) of Other alleles. This variant has been detected as homozygous, heterozygous, and in conjunction with a ABCB4 variant of unknown significance in multiple individuals with clinical features of ABCB4 deficiency (Poupon, 2010; Dixon, 2017; Huynh, 2019; Khabou, 2019; Huynh, 2019; Almes, 2022). This amino acid position is highly conserved in available vertebrate species. A functional study shows the alteration results in reduced expression compared to wild type ABCB4 (Frider, 2015). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004537459	SCV004120131	likely pathogenic	ABCB4-related disorder	2022-11-28	criteria provided, single submitter	clinical testing	The ABCB4 c.140G>A variant is predicted to result in the amino acid substitution p.Arg47Gln. This variant was reported in the compound heterozygous or homozygous states in individuals with low phospholipid associated cholelithiasis (Wendum et al 2012. PubMed ID: 22331132; Frider et al 2015. PubMed ID: 26256905; Poupon et al. 2013. PubMed ID: 23533021; Khabou et al. 2019. PubMed ID: 31181191) and functional studies indicated that it may cause reduced protein levels (Frider et al 2015. PubMed ID: 26256905). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-87092220-C-T). Taken together, we classify this variant as likely pathogenic.